Sympatholytic compositions



Patented Jan. 16, 1951 SYMPATHOLYTIC COMPOSITIONS Louis Sanford Goodmanand Mark Nickerson, Salt Lake City, Utah, assignors to Burton T. Bush,Inc., New York, N. Y., a corporation of New Jersey No Drawing.Application February 6, 1946, Serial No. 645,961

8 Claims. (Cl. 167-65) the importance of sympatholytic agents in thetreatment of disease. The treatment of high blood pressure represents acrucial medical problem even today. This can easily be appreciated whenit is noted that one out of three of all people over fifty years of agedie of some disease related to the heart and blood vessels. At present,an operation known as the Smithwick operation is sometimes performed inthe treatment of high blood pressure. This operation involves removal ofcertain parts of the sympathetic nervous system. Our present inventionmakes it possible to accomplish the desired purpose without anyoperation at all. In addition to eliminating the ordeal of such anoperation, our present invention also avoids the consequences of theoperation, namely, the permanent loss of the excised parts, inasmuch asthe effects of our drugs can be eliminated by stopping theiradministration.

Again, in the treatment of certain types of diseases of the bloodvessels of the arms and legs (peripheral vascular disease), operation onthe sympathetic nervous system is often done, and this condition toocould be treated medically in accordance with the present invention.

Also, in the use of the excellent anesthetic, cyclopropane, one of thegreat dangers to the patient, sometimes resulting in death, is theefiect of cyclopropane on the heart, in the presence of even minuteamounts of epinephrine or in the presence of overactivity of thesympathetic nervous system. A sympatholytic drug given to a patient towhom cyclopropane had been administered as an anesthetic would protecthim against the harmful effects of cyclopropane on the heart, therebyallowing cyclopropane anesthesia to be safe as well as efficient.

Before proceeding to identify the novel sympatholytic and adrenolyticagents, we believe it will aid to a better understanding of ourinvention if we set forth some remarks concerning the nervous system andthe action of sympatholytic agents thereon.

In the more highly organized forms of life the nervous system isindispensable for existence and is necessary in order to keep theinternal environment of the organism constant and to allow adaptation ofthe organism to its environmental surroundings. In'mammals the nervoussystem is divided into two large parts, the somatic nervous systemconsisting of the brain, spinal cord and peripheral nerves, and theautonomic or visceral nervous system. The central nervous systemcontrols such processes as thought, locomotion and sensation, as well asemotion. The visceral nervous system is concerned with regulating allthe autonomic functions of the body including heart rate, bloodpressure, circulation of blood to different parts of the body, secretionand motility of the stomach and intestine, size of the pupil, sweating,temperature control, respiration, urinary tract function, etc. It isalso concerned with cum-- tions, particularly in joy, anger and fear.Life would be impossible without the visceral nervous system which isalso intimately connected anatomically and physiologically to thecentral nervous system.

The visceral nervous system is likewise traditionally divided into twoparts, one known as the sympathetic nervous system and the other as theparasympathetic nervous system. Most organs of the body are suppliedbynerves from both of these divisions and as a general rule the actions ofthese nerves stand in opposition. For example, the sympathetic nervoussystem causes dilatation of the pupil of the eye whereas theparasympathetic nervous system causes constriction. Again, theparasympathetic nervous system causes slowing of the heart beat whereasthe sympathetic nervous system causes speeding of the heart rate. Thesympathetic nervous system causes constriction of blood vessels and arise in blood pressure, whereas the parasympathetic system causesdilatation of blood vessels and a fall in blood pressure. The intestinaltract is stimulated by the parasympathetic system and relaxed by thesympathetic system;

Within the last twenty years it seems to have been definitelyestablished that when a nerve impulse travelling over a nerve reachesthe muscle cell or gland cell, a chemical substance is released whichacts on the muscle or gland cell causing it to respond in itscharacteristic fashion. In the sympathetic system this chemicalsubstance is known as sympathin, and perhaps is identical with thehormone of the adrenal medulla gland which is called adrenalin orepinephrine. In the parasympathetic nervous system the chemical is knownas acetylcholine. In other words these two chemicals, acetylcholine andepinephrine, when given to animals or man will 'result in the same typeof bodil reactions as caused by stimulation, respectively, of theparasympathetic and sympathetic nervous systems. Indeed, in the body,the sympathetic nervous system discharges not only sympathin but alsoepinephrine from the adrenal medulla.

Compositions which are the subject of this inventiion act in the body toprevent the usual excitatory action of either the sympathetic nervoussystem or epinephrine. In other words, an animal given the proper doseof these drugs will be protected against the effects of sympatheticnerve impulses of an excitatory nature and alsoagainst the excitatoryeffects of epinephrine, whether the latter is normally secreted in "thebody or injected by the physician.

Many diseases, syndromes, and symptoms experienced by patients arerelated to abnormal functions of the parasympathetic or sympatheticnervous'system or to an imbalance between these two systems. in theparasympathetic field, ex- 'cellentdrugs such "as the belladonnaalkaloids are available to cause a blocking of either acetylc'h'oline orparasympathetic nerve impulses. In the sympathetic held, no such drug isavailable. Indeed, as aforesaid, though some drugs have been suggestedin this field, they have not "been found to be suitable, because theyare too toxic '"to be used extensively in man, becausethey are notsufficiently potent, or because they have so many side-effects that nospecificity of action 'can he'obtained.

The compositions described herein are known as sympatholytic andadren'olytic compounds'because they prevent 'the previously describedactions of the sympathetic nervous system and adrenalin.

The novel sympatholytic and adrenolytic agents provided-by thisinvention and having the above-indicated applications and uses includecertain amines and their quaternary compounds as well as their saltswith inorganic and organic acids. More specifically, these novel agentscan be represented by the :following general structural formula:

wherein R1 is a member selected from the group consisting o1 H and CH3,R2 is a member selected from the group consisting of H, alkyl, aralkyl,aryl, =haloalkylene and cycloalkyl radicals, Eris ta member selectedfrom the group consisting of 1-1 and-CH3, and X is halogen; organic andinorganic salts of said compounds; and quaternary salts "of saidcompounds.

As specific examples of our novel sympatholytic :and -a'drenolyticagents the following may be noted:

CHr-OHr-Cl ot. a 6 C '7. Hydro-chlorides'of "compounds #:1 to 5- above,

'8. 'Hydrobromide of compound #6 above,

9. Salts of compounds #1 to 6 with acetic acid, 10. Salts of compounds#1 to 6 withbenzoic acid, ll. Salts of-compounds #1 to 6 with nitricacid, 12. Quaternary salts of compounds #1 to 6 with dimethyl sulfate orethyl bromide.

The novel sympatholytio and adrenolytic compositions of this inventionmay be administered orally or parenterally. Theymay be employed in theiorm of tablets, made by incorporating inert .carriers in the activeingredients, capsules, solutions, etc. For parenteral injections theWater soluble compounds may be administered in the .form of aqueoussolutions. The non-water soluble saltsmay be administered in thepresenceof suitable solvents, as, for example, in the form of a 10%solution of the salts in propylene glycol.

'Such solution should be mixed with aqueous sodium chloride (0.9%) priorto intravenous injection.

The sympatholytic and adrenolytic agents herein have Varying physicaland chemical properties, depending, inter alia, on their structure, e.g., whether they are amines, salts with inorganic and organic acids, orquaternary ammonium salts. The amines are not water-soluble, but may bedissolved in ethyl alcohol, propylene glycol, and oxygenated solventsgenerally. The salts made with inorganic and organic acids are generallysomewhat Water-soluble, and also somewhat soluble in organic solventssuch as those just mentioned. The quaternary salts are Water-soluble andgenerally soluble in polar organic solvents.

In order to illustrate this invention more fully, but Without therebylimiting it, the following examples are given.

EXAMPLE I Dibeneyl-beta-chloroethylamine hydrochloride To 610 grams ofmonoethanolamine, 1265 grams of benzyl chloride are added understirringdur- .ingfive hours at ,a temperature of 100-ll0-.C. Stirring andheating at 100-ll0 C. is continued for live more hours.

After cooling to about C'., a solution of 400 grams of sodium hydroxidein 600 cc. of water was gradually added under stirring and the mixturewas heated in a boiling water bath for one hour. After cooling to roomtemperature, the contents were extracted with 800 cc. of benzene. Thebenzene solution was separated, washed with 1000 cc. of water, driedwith anhydrous sodium sulfate and filtered. J The benzene was removed bydistillation first under atmospheric pressure to a temperature of 90 0.,and finally under vacuum of about 30 mm. mercury to about 100 C. Theresidual oil was then distilled at a vacuum of mm. mercury and 848 gramsof the desired material, boiling at 185-192 C., were obtained. Theliquid solidified on standing to a crystalline solid, congealing at 43C.

A solution of 482 grams of dibenzyl aminoethanol in 500 cc. ofchloroform was cooled in an ice bath and under stirring, a solution of2'76 grams of thionyl chloride in 300 cc. of chloroform was added duringtwo hours. Stirring was then continued for three hours under cooling.The reaction mixture was allowed to stand over night. The chloroform wasdistilled off under atmospheric pressure except near the end when vacuumwas employed, and the crystalline mass was recrystallised from 700 cc.of ethanol containing grams of decolorizing carbon. After filtration,410 grams of white crystals of dibenzyl beta chloroethylaminehydrochloride, melting at 194-l95 C. were obtained; addition of ether tothe mother liquor yielded a second crop of 90 grams (melting point192-194 0.).

Parenteral administration in man: this compound is dissolved inpropylene gylcol (sterile technic) to the extent of 10%. It is stable inthis solvent if the solution is acidified with anhydrous sulfuric acid(1:200 final concentration). Injection is made slowly intravenously(either by syringe technic directly or by injection into the tubing ofan intravenous saline or glucose infusion) after dilution with 0.9%sodium chloride solution to at least 1:10. Evidence of physiologicaleffect can usually be detected within 10 to minutes, as indicated byparalysis of adrenergic excitatory effector cells. For example, thepupils become constricted, the peripheral vessels dilate ifsympathetically constricted, the heart and blood vessels do not respondas before to sympathetic nerve impulsesor to administered epinephrine,etc. Dosage: 5 to 10 mg./kg. per single dose. Effects may last severaldays.

Cats, rats and mice have been given this compound orally, acutely(single doses) and chronically (daily for as long as eight days), thedose used ranging from 5 to 20 times the intravenous dose. Effectiveoral doses are in the neighborhood of 5 times the parenteral dose. Theaction takes approximately an hour to become manifested and persists fordays, even after a single dose.

Similar pharmacological results may be obtained with the materialsprepared in accordance with the following examples.

EXAMPLE II Dibeneyl-beta-chloroethylamine 300 grams of finely powdereddibenzyl-betachloroethylarnine hydrochloride, prepared in accordancewith Example Lwere vigorouslyv stirred for a half hour with 500 cc. of asaturated aqueous solution of potassium carbonate. The mixture wasshaken with 400 cc. of benzene and the resulting benzene-containinglayer was dried with anhydrous sodium sulfate filtered, and the solventwas removed by distillation. The residual oil was distilled under highvacuum.

The desired dibenzyl-beta-chloroethylamine (210 grams) was obtained inthe form of a yellowish oil, boiling at 176-l80 C. at 4 mm. Hg.

6 EXAMPLE III Di-paramethyl benzyl-beta-chloroethylaminehydrochloride Ina similar manner as in Example I, di-pvmethylbenzyl amino ethanol(boiling point 205- EXAMPLE IV I BenzyZ-ethyZ-beta-chloroethylaminehydrochloride Benzyl chloride (253 grams) were dropped into ethylmonoethanolamine (356 grams) during two hours under stirring at atemperature of (3., and the mixture was kept at this temperature for sixhours. A saturated solution of 150 grams of potassium carbonate was thenadded and after stirring and cooling, the reaction mixture was extractedwith 500 grams of isopropyl ether. The isopropyl ether solution wasdried over anhydrous sodium sulfate and distilled. After removal of theisopropyl ether, the residue was distilled at 10 mm. through a smallVigreux column. Obtained were 143 grams, boiling point 12'7-1.35 C. andrefractive index 20, 1.5175 and 220 grams, boiling point C. andrefractive index 1.5190. The two fractions were combined for thepreparation of the betachloroethyl derivative.

A solution of 190 grams of thionyl chloride in 100 cc. of chloroform wasdropped under stirring into a solution of 268 grams of benzyl ethylaminoethanol in 300 cc. of chloroform which mixture was cooled in an icebath. The time for the addition was about two hours, stirring was thencontinued for three hours under cooling. The reaction mixture wasallowed to stand over night. The chloroform was then distilled off onthe water bath, applying low vacuum at the end. 100 cc. of ethanol wereadded and the mixture evaporated to dryness in vacuo. The crystallineresidue was dissolved in 300 cc. of isopropanol and the solutionrefluxed for about half an hour under the addition of 5 gramsdecolorizing carbon. To the filtered and cooled solution, petroleumether (boiling point 60-90 C.) was added until crystals started toseparate. The crystals of benzyl ethylbeta-chloroethylaminehydrochloride formed after standing were filtered, washed with petroleumether and dried (300 grams, melting point 154-l55) EXAMPLE VBenzyl-ethyl-betd-chlorocthylamine In accordance with the procedure ofExample II, benzyl ethyl-beta-chloroethylamine (boiling point 114-115 C.at 4 mm. Hg) was obtained from its hydrochloride (prepared as in ExampleIV).

1 EXAMPLE VI DibenzyZ-beta-chloropropyla'mine hydrochloride Into gramsof isopropanolamine, heated to 100 C. were dropped under stirring 253grams of benzyl chloride during two hours; the mixture was then kept at100-110 C., for five hours. A concentrated solution of 90 grams ofsodium hydroxide was then added and the reaction product extracted with600 grams of benzene. The benzene solution was washed with water, driedover 7 anhydrous sodium sulfate and distilled. After removal of thebenzene, the residual oil was distilled in vacuo and .1I68grams ofdibenzyl amino isopropanol, boiling point 170-175 C., were collected.

Dibenzyl amino isopropanol (1'27 grams) were dissolved in 100 cc. ofchloroform and cooled in an ice salt bath. To this solution, '70 gramsof thionyl chloride in 100 cc. of chloroform were added under stirringduring two hours. Stirring was-thencontinued for another three hoursunder cooling. The reaction mixture was allowed to stand over night. Thechloroform was distilled off, applying low vacuum at the end. Ethanolcc.) Was added and the mixture evaporated to dryness in vacuo. Thecrystalline residue was dissolved in cc. of isopropanol and the solutionpurified by addition of 2 grams of decolorizing carbon and refluxing forthirty minutes. The filtered and cooled solution was brought tocrystallisation by adding isopropylether. 92 grams of white crystals,melting at 165-167 were obtained.

EXAMPLE VII Dibenzybbetawhloropropylamine In accordance with theprocedure of Example II dihenzyl beta chloropropylamine (boiling pointl76-177 C. at 3 mm. Hg) was obtained from its hydrochloride (prepared asin Example VI).

EXAMPLE VIII Beneyl dzf-beta-chloroethylamine hydrochloride .Benzylchloride (190 grams) was slowly dropped under stirring intodiethanolamine (315 grams), heated to 100 C. During the addition whichtook about one hour, the temperature rose to 125 C. Stirring wascontinued at this temperature for eight hours. Sufficient saturatedpotassium carbonate solution to neutralize the formed hydrochlorides wasadded and the mixture stirred for thirty minutes at C. An oil separated;extraction with isopropyl ether (-500 cc.) dissolved only small amountsof this oil. The oil and the isopropyl ether fraction were combined andenough ethanol added to obtain a horrlcgeneous mixture. This solutionwas dried over anhydrous sodium sulfate and distilled. After removal ofthe solvent, the oil was distilled through a Vigreux column in vacuo.The fraction boiling at 174L183 C. at 6 mm. was redistilled and 162grams of pure di-beta-hydroxyethylbenzyla-mine, boiling point 1'7617'7C. were obtained.

Into 97 grams of di-betahydroxyethyl benzyl amine, dissolved in cc. ofchloroform, and cooled with water, were dropped in under stirring 120grams of thionyl chloride dissolved in 100 cc. of chloroform. The sameprocedure as described for benzyl ethyl-beta-chloroethylaminehydrochloride was applied, except that ethyl ether was used in place ofpetroleum ether, and grains of white, crystalline di-beta-chloroethylbenzylamine hydrochloride, melting at 1/l8-15(l C were obtained.

EXAMPLE IX Benet/Z di-beta-chloroethylamine In accordance with theprocedure of Example II, di beta chloroethylbenzylamine (boiling point148150 C. at 4 mm. Hg) was obtained from its hydrochloride (prepared asin Example VIII).

- EXAMPLE 2:

Di-benzyl-beta-bromoethylamine hydrobromide in vacuo-and twicerecrystallised from alcohol (50 cc.) under addition of ether untilcrystals sepa rated. White crystals of dibenzyl-beta-bromoethylaminehydrobromide (38 grams) of melting point 176- 178 C. were obtained. Theanalysis showed 41.6% Br (theory 41.8%).

EXAMPLE XI Di-benzyZ-beta-bromoethylamine In accordance with theprocedure of Example II, -di-benzyl-beta-bromoethyl amine (boiling point177l78 C. at 3 mm. Hg) was obtained from its hydrobromide (prepared inaccordance with Example X) EXAMPLE XII Beta-chloroethyZ-dibenzyZ-methylammonium methosulfate 13 grains of dibe11zyl-beta-chloroetl1yl amine(prepared as in Example II), 14 grains of dimethyl sulfate and 40 odor"specially denatured #30 alcohol were boiled for 4 hours. The corrtentswere passed into 200 cc. of ethyl ether under stirring, and thenpermitted to stand for a half hour. The ether was decanted and theresidue was twice washed with 56 cc. of ethyl ether by thorough shakingfollowed by decantation of the supernatant liquid after settling. Theresulting viscous oil was dried under high vacuum (4 mm. He) at 90 C.for one hour.

21 grams of a viscous brown oil were obtained. It is soluble in water,alcohol, acetone and propylene glycol, and insoluble in aromatic andpetroleum hydrocarbons.

EXAMPLE EQIII DibenzyZ-beta-bromoethyZ-methylammonium methosulfate Inaccordance with the procedure of Example XII,dibenzyl-betabromoethyl-methyl-ammonium methosulfate in the form of abrownish, very viscous liquid, was obtained from its amine (prepared inaccordance with Example XI). This liquid is soluble in water, ethylalcohol, methyl alcohol, acetone, propylene glycol, but is insoluble inethyl ether, benzene and petroleum ether.

EXAMPLE EHV 'Benzy'Z-di-beta-chloroethyl-methylammonium methosulfate Inaccordance with the procedure of Example XII, the above named materialwas obtained from its amine (prepared in accordance with Example IX) inthe form of a brownish, very Viscous liquid. This liquid is soluble inwater, ethyl alcohol, methyl alcohol, acetone, propylene glycol, but isinsoluble in ethyl ether, benzene and petroleum ether.

9 EXAMPLE xv ammo- In accordance with the procedure of Example XII, theabove named material was obtained from its amine (prepared in accordancewith Example V), in the form of a brownish, very viscous liquid. Thisliquid is soluble in water, ethyl alcohol, methylalcohol, acetone,propylene glycol, but is insolublein ethyl ether, benzene and petroleumether.

EXAMPLE XVI Dibenzyl-beta-chloropropyZ-methyl ammonium methosulfate Inaccordance with the procedure of Example XII, the above named materialwas obtained from its amine (prepared in accordance with Example VII, inthe form of a brownish, very viscous liquid. This iliquid is soluble inwater, ethyl alcohol, methyl alcohol, acetone, propylene glycol, but isinsoluble in ethyl ether, benzene and petroleum ether. 1 I

The foregoing illustrates the practice of this invention, which however,is not to be limited thereby but is to be construed as broadly aspermissible in view of the prior art and limited solely by the appendedclaims.

What is claimed is:

1: Therapeutic compositions having sympatholytic and adrenolyticproperties, comprising propylene glycol and at least one materialselected from the group consisting of salts of organic and inorganicacids with amines having the following general structural formula:

ammonium salts of said amines.

2. Therapeutic compositions having sym patholytic and adrenolyticproperties, comprising dibenzyl-beta-chlorethylamine hydrochloride andpropylene glycol.

3. {Therapeutic compositions having sympatholytic and adrenolyticproperties comprising non-toxic, organic oxygenated solvent and at leastone material selected from the group consisting of salts of organic andinorganic acids with amines having the following general structuralformula:

Ra Ra wherein R1 is a member selected from the group consisting of H andCH5, R2 is a member selected from the group consisting of H, alkyl,aryl, aralkyl and haloalkyl radicals, Rs is-a member selected from thegroup consisting of H and CH3, and X is a halogen selected from thegroup consisting of chlorine and bromine; and quaternary ammonium saltsof said amines.

4. Therapeutic compositions having sympatholytic and adrenolyticproperties, comprising dibenzyl-beta-chlorethylamine hydrochloride andnon-toxic, organic oxygenated solvent.

5. Therapeutic compositions having sympatholytic and adrenolyticproperties, comprising di-paramethylbenzyl-betachloroethylaminehydrochloride and propylene glycol.

6. Therapeutic compositions having sympatholytic and adrenolyticproperties, comprising benzyl-ethyl-betachloroethylamine hydrochlorideand propylene glycol.

7. Therapeutic compositions having sympatholytic and adrenolyticproperties, comprising dibenzyl-beta-chloropropylamine hydrochloride andpropylene glycol.

8. Therapeutic compositions having sym patholytic and adrenolyticproperties, comprising dibenzyl-beta-bromoethylamine hydrobromide andpropylene glycol.

LOUIS SANFORD GOODMAN. MARK NICKERSON.

REFERENCES CITED The following references are of record in the file ofthis patent:

FOREIGN PATENTS Number Country Date 436,793 Great Britain Oct. 14, 1935538,456 Germany Nov. 13, 1931 550,762 Germany May 20, 1932 OTHERREFERENCES Orth et al.: Squibb Abstract Bulletin, vol. 12, page 1194,Sept. 27, 1939. (Copy in Div. 43.)

Suter et al.: J. A. C. S. 63. 602-4 (1941). (Copy in P. O. S. L.)

J. A. P. A. Prac. Pharm Ed., June 1943, pp. 194, 195. (Copy in P. O. S.L.)

Introzzi: Squibb Abstract Bull, vol. 16, page 1964 (1943). Copy in Div.43.

Jacobson et al.: J. A. M. 11., Oct. 5, 1946, page 263. (Copy in P. O. S.L.)

3. THERAPEUTIC COMPOSITIONS HAVING SYMPATHOLYTIC AND ADRENOLYTICPROPERTIES COMPRISING NON-TOXIC, ORGANIC OXYGENATED SOLVENT AND AT LEASTONE MATERIAL SELECTED FROM THE GROUP CONSISTING OF SALTS OF ORGANIC ANDINORGANIC ACIDS WITH AMINES HAVING THE FOLLOWING GENERAL STRUCTURALFORMULA: